Bone contains two distinct cell lineages, i.e. bone-forming cells (e.g. osteoblasts) and bone-resorbing cells (e.g. osteoclasts). Bone is a dynamic tissue that is continuously being destroyed (resorbed) and rebuilt, by an intricate interplay between these osteoblasts and osteoclasts. For osteoclasts, a cascade of transcription factors and growth factors involved in the progression from progenitor cell to functional osteoclast is well established. In contrast, little is known about the osteoblast lineage.
Osteoblasts derive from differentiated mesenchymal progenitor cells (MPCs). During the differentiation into osteoblasts bone alkaline phosphatase activity (BAP) becomes upregulated. Bone formation in vivo occurs through two distinct pathways during embryonic development: endochondral or intramembranous ossification (FIG. 1). As shown in this figure, mesenchymal progenitor or stem cells represent the starting points for both forms of bone formation. During intramembranous ossification, flat bones such as those of the skull or clavicles, are formed directly from condensations of mesenchymal cells. During the formation of long bones, such as limb bones, mesenchymal condensations first lead to a cartilage intermediate that is invaded during further development by endothelial cells, osteoclasts and mesenchymal cells that will differentiate into osteoblasts and osteocytes (Nakashima and de Crombrugghe, 2003).
A number of diseases are known which are caused by a disturbance of the fine-tuned balance between bone resorption and bone build-up, which skeletal diseases represent a large number of patients: hypercalcemia of malignancy, Paget's disease, inflammatory bone diseases like rheumatoid arthritis and periodontal disease, focal osteogenesis occurring during skeletal metastases, Crouzon's syndrome, rickets, opsismodysplasia, pycnodysostosis/Toulouse-Lautrec disease, osteogenesis imperfecta, and the single most important bone disease: osteoporosis.
Currently, osteoporosis affects 1 in 5 women over 50 and 1 in 20 men over 50. For these patients a number of treatments are available, which mostly tackle the net increase in bone resorption, i.e.:
hormone replacement therapy (HRT)
selective estrogen receptor modulators (SERMs)
bisphosphonates
calcitonin
While these treatments slow down bone resorption, they do not abolish fracturing because the lost bone is not sufficiently replenished. Fracturing will be stopped when bone formation is sufficiently increased. Therefore, there is great interest in identifying osteogenic pathways that lend themselves to therapeutic intervention with bone anabolism as effect. Currently, only one bone anabolic therapy has reached the osteoporosis market: parathyroid hormone (PTH) 1-34. PTH displays bone anabolic effects when administered intermittently. The treatment with PTH is, however, very cumbersome because this biopharmaceutical needs to be injected daily by the patient. In addition, tumor formation has been observed when treating animals at high doses. Also, it is a very expensive treatment.
Another class of bone anabolics, bone morphogenetic proteins (BMPs), have been approved but only for niche markets, as there are disadvantages to their use as therapeutic agents to enhance bone healing. Receptors for the bone morphogenetic proteins have been identified in many tissues, and the BMPs themselves are expressed in a large variety of tissues in specific temporal and spatial patterns. This suggests that BMPs may have effects on many tissues other than bone, potentially limiting their usefulness as therapeutic agents when administered systemically.
Accordingly, there is a continuing need for novel treatment strategies and compounds (in particular anabolics) that obviate one or more of the drawbacks of the currently available treatment strategies.